Recent developments in microarray technology have made it possible to contemplate simultaneously analyzing many hundreds of thousands of individual genetic elements within a single nucleic acid sample. There already exists technology in which probe arrays containing several hundred thousand oligonucleotides are present on a single glass chip (1 cm.sup.2). (Wang, D. G., et al., Science, 280:1077-1082 (1998)). However, this increase in synthesis capability has exceeded the capacity of polymerase chain reaction (PCR) amplification technology to provide hybridization targets. For example, a microarray containing probes for 10.sup.4 randomly distributed human single nucleotide polymorphisms (SNPs) could be used to generate a detailed genomic map of a single individual in a single hybridization experiment. Currently, it is extremely difficult to amplify more than 100 independent loci in a single PCR reaction. (Wang, D. G., et al., Science, 280:1077-1082 (1998)). Therefore, using current PCR technology, at least 100 individual PCR reactions, each reaction amplifying 100 distinct loci, must be performed and pooled to take full advantage of a 10.sup.4 loci SNP typing chip.
Similar difficulties are anticipated for other multiplex genotyping technologies, such as mass spectrometry. (Hall et al. Nature Biotechnology, 16:1352-1365 (1998), and Fu et al., Nature Biotechnology, 16:381 (1998)). For this reason, there is a need for new methods that enable massively multiplex nucleic acid amplification. Ideally, such methods would make it possible to produce 10.sup.3 to 10.sup.4 different products in a single reaction. Coupled with microarray or multiplex mass spectrometry typing methods, such multiplex amplification methods would make it possible to rapidly generate high density, whole genome SNP maps for large numbers of individuals. This would immediately accelerate genetic research in many areas including genetic analysis of complex traits (e.g., asthma, high blood pressure, and various forms of heart disease), human genetic disease research, pharmacogenomics and cancer biology. Improved multiplex amplification methods would also greatly facilitate analysis of gene expression.